Role of meprin metalloproteinases in cytokine processing and inflammation

Abstract

Meprin metalloendopeptidases, comprising α and β isoforms, are widely expressed in mammalian cells and organs including kidney, intestines, lungs, skin, and bladder, and in a variety of immune cells and cancer cells. Meprins proteolytically process many inflammatory mediators, including cytokines, chemokines, and other bioactive proteins and peptides that control the function of immune cells. The knowledge of meprin-mediated processing of inflammatory mediators and other target substrates provides a pathophysiologic link for the involvement of meprins in the pathogenesis of many inflammatory disorders. Meprins are now known to play important roles in inflammatory diseases including acute kidney injury, sepsis, urinary tract infections, bladder inflammation, and inflammatory bowel disease. The proteolysis of epithelial and endothelial barriers including cell junctional proteins by meprins promotes leukocyte influx into areas of tissue damage to result in inflammation. Meprins degrade extracellular matrix proteins; this ability of meprins is implicated in the cell migration of leukocytes and the invasion of tumor cells that express meprins. Proteolytic processing and maturation of procollagens provides evidence that meprins are involved in collagen maturation and deposition in the fibrotic processes involved in the formation of keloids and hypertrophic scars and lung fibrosis. This review highlights recent progress in understanding the role of meprins in inflammatory disorders in both human and mouse models.

Keywords: CCL2; IL-18; IL-1β; IL-6; IL-6R; Inflammation; Meprin A; Meprin α; Meprin β; Metalloproteinase.

Figure 1:

Structural domains and oligomeric forms of meprin α and β. Structural domains of meprins include an N-terminal signal peptide, propeptide, protease domain (HExxHxxGxxH), MAM (meprin A5 protein receptor protein tyrosine phosphatase μ), TRAF (tumor necrosis factor receptor-associated factor), AM (after MATH), I (inserted domain), EGF (epidermal growth factor -like), TM (transmembrane spanning), and cytoplasmic domain. Meprin β is a membranebound protease. Meprin subunits composed of α2β2 heterotetramer form Meprin A which is bound to membranes through meprin β. The meprin subunits are bound together by disulfide bridges (horizontal black bars). Meprin α oligomerizes to become a higher molecular mass soluble from of protease and is secreted as a homooligomer.

Figure 2:

Sites of cleavage by meprins in pro-IL-1β, pro-IL-18, CCL2/MCP-1, and IL-6R. Cleavage sites of meprin A, meprin α, and meprin β, in the pro-IL-1β sequence were analyzed as described [22, 23]. Meprin A and meprin α cleave pro-IL-1β at the His¹¹⁵-Asp¹¹⁶ peptide bond and meprin β cleaves at As n¹¹⁰-Glu¹¹¹ peptide bond. Cleavage sites of heteromeric meprin A and meprin β in the pro-IL-18 at the Asn⁵¹-Asp⁵² peptide bond were determined as described [26]. Cleavage sites of meprin α, heteromeric meprin A, and meprin β for CCL2/MCP-1 were analyzed as described [20]. Meprin α and meprin A cleaves the N-terminal domain at the Asn⁶-Ala⁷ bond and meprin β cleaves the C-terminal region between Ser⁷⁴ and Glu⁷⁵ of mouse CCL2/MCP-1. Meprin α and β cleave and membranebound IR-6R at the Gln³⁵⁷-Asp³⁵⁸ peptide bond as described [25].

Figure 3:

Processing of cytokines and procollagens by meprins. Membrane-bound meprin β can be shed by ADAM 10. Following activation by trypsin-like serine proteases, shed meprin β can process pro-IL- 1β and pro-IL-18 to their active forms. Meprin α can also process pro-IL-1β to its active form. The active cytokines then bind thei r receptors to transduce NF-kB and MAPKs signaling. Membrane bound meprin β may be activated by matriptase-2 (not shown). Meprin α and β can also cleaves ectodomain of IL-6R to produce soluble IL-6R that promotes IL-6 trans-signaling. Meprin α and β can process N- and C-termini of procollagen I and III resulting in the collagen maturation and formation of collagen fibrils.

Figure 4:

Schematic diagram depicting the involvement of meprins in organs and cells. Meprins are expressed in various organs and cells and regulate pathophysiologic outcome as shown.